W. DALTON DIETRICH, PH.D.

Neuroprotection and Improved Recovery of Function following CNS Trauma

Research Interests

My research interest is the pathobiology and treatment of CNS injury in both the acute and chronic setting. Animal models of cerebral ischemia, and brain and spinal cord trauma are utilized to investigate the mechanisms of tissue injury. The ultimate goal is to target specific injury processes for pharmacological intervention, including the addition of growth factors, to promote circuit plasticity, regeneration and recovery of function.

Recent studies have demonstrated the neuroprotective effects of moderate hypothermia following traumatic brain injury. Brain cooling has been shown to protect the brain histopathologically and to improve functional outcome. These experimental studies have led to the initiation of clinical trials for hypothermia in humans in traumatic brain and spinal cord injury. Studies are currently in progress to demonstrate the potential benefits of hypothermia following spinal cord injury. In contrast to hypothermia, brain hyperthermia following ischemia and trauma significantly aggravates outcome. Thus, fever appears to be a potentially severe secondary injury mechanism that must be avoided in head or spinal cord injured (SCI) patients.

Various potentially neuroprotective agents are currently being tested in models of CNS trauma. Nitric oxide (NO) produced at high levels following CNS injury can act as a free radical intermediate and produce cytotoxicity. Ongoing studies are investigating novel way to target abnormal NO production by inhibiting inducible nitric oxide synthase (iNOS) early after SCI. In this regard, both pharmacological and gene therapeutic inhibition of iNOS appear to be neuroprotective and enhance behavioral recovery after CNS injury.

The neurotrophic factor, basic fibroblast growth factor (bFGF), has recently been shown to be neuroprotective in models of cerebral ischemia and traumatic brain injury. These experimental data have led to the initiation of a multicenter clinical trial of bFGF in acute stroke patients. In addition to neuroprotection, various strategies are being shown to promote recovery of function when given days after the primary insult. Recent animal studies have demonstrated that bFGF given 24 hours after focal ischemia accelerates recovery of function. Importantly, bFGF-induced improved functional recovery appears to be associated with brain circuit reorganization. Thus, the possibility exists that in chronic injury states, such as spinal cord injury, neurotrophic factors may be given to induce circuit rewiring and, thus, improve outcome. Studies are currently underway to determine the specific mechanisms by which bFGF and other neurotrophic factors improve outcome in models of spinal cord injury.